EFFICACY OF KETAMINE AND ESKETAMINE IN TREATMENT-RESISTANT DEPRESSION AMONG OLDER ADULTS (≥65 YEARS): A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED AND REAL-WORLD STUDIES (2023–2025).
Shimul A. Babli*1 Huijuan Song2 Sharmin Ferdous3 Farzana Rahman4 Dilyaver Matakhov5 Hannah Jeyakkodi6
Zenodo (CERN European Organization for Nuclear Research) May 1, 2026 preprint DOI: 10.5281/zenodo.19947544 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Randomized |
|---|---|
| Population | Adults aged 65 years and older with treatment-resistant depression |
| Interventions | Ketamine Esketamine |
| Topics | Depression Esketamine Ketamine |
| Key findings | Ketamine and esketamine were associated with large, clinically meaningful reductions in depressive symptoms in older adults with treatment-resistant depression, with a pooled standardised mean change of −1.68 (95% CI −1.85 to −1.51). About 47 per cent experienced at least one adverse event, mostly mild, and 16 per cent discontinued due to adverse events. The authors conclude the agents appear effective and reasonably well tolerated but call for further geriatric-focused randomised trials. |
Abstract
Late-life treatment-resistant depression (TRD) poses substantial clinical challenges, with limited effectiveness of conventional antidepressants and heightened vulnerability to adverse effects among older adults. Ketamine and esketamine have emerged as rapid-acting antidepressants, but their efficacy and safety in geriatric populations remain incompletely characterised. A systematic review and meta-analysis were conducted to evaluate ketamine and esketamine for TRD in adults aged ≥65 years. Thirteen primary studies published between 2023 and 2025 were included. Standardised mean change (SMC) was used to estimate antidepressant effects, while adverse events (AEs) and discontinuation rates were synthesised using random-effects models. Risk of bias was assessed using ROBINS-I and RoB 2 tools, and publication bias was evaluated through funnel plot analysis. Ketamine and esketamine produced large and clinically meaningful reductions in depressive symptoms, with a pooled SMC of −1.68 (95% CI −1.85 to −1.51). Approximately 47 per cent of older adults experienced at least one AE, although most events were mild. Discontinuation due to AEs was low, with a pooled rate of 16 per cent (95% CI 0.14–0.18). Risk-of-bias assessments varied across studies, but randomised trials demonstrated consistently low risk. Funnel plot analysis revealed no evidence of significant publication bias. Ketamine and esketamine appear to be effective and reasonably well tolerated in older adults with TRD. Further geriatric-focused randomised trials are needed to refine dosing, monitor long-term outcomes, and guide clinical decision-making.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation | 2020 | Systematic review and meta-analysis | n = 197 |
| Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal | 2020 | Systematic review and meta-analysis | n = 774 |
| Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder | 2025 | Systematic review and meta-analysis | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |